REEP6 (receptor accessory protein 6) is essential for photoreceptor survival and retinal homeostasis. In rod photoreceptors, REEP6 maintains endoplasmic reticulum (ER) and mitochondrial homeostasis while facilitating stability and trafficking of guanylate cyclases (GC1/GC2) 1. The retina-specific REEP6.1 isoform is critical for rod function; loss of this isoform causes progressive photoreceptor degeneration from postnatal day 20 2. Mutations in REEP6 cause autosomal recessive retinitis pigmentosa 77, with variants destabilizing the protein and triggering ER stress via caspase 12 activation 3. Gene replacement therapy with rAAV8-Reep6.1 effectively preserves photoreceptor function in mutant mice for extended periods 4. Beyond retinal function, REEP6 acts as a ferroptosis suppressor in oral squamous cell carcinoma by maintaining ER homeostasis and regulating ACSL4 expression, with overexpression associated with poor survival 5. REEP6 also enhances CXCR1-mediated signaling in lung cancer by facilitating ligand-stimulated endocytosis rather than membrane expression 6. These findings establish REEP6 as a multifunctional protein critical for photoreceptor homeostasis and implicated in cancer progression through ER stress regulation.